MOLECULAR-GENETICS OF CYSTINURIA - IDENTIFICATION OF 4 NEW MUTATIONS AND 7 POLYMORPHISMS, AND EVIDENCE FOR GENETIC-HETEROGENEITY

A cystinuria disease gene (rBAT) has been recently identified, and som e mutations causing the disease have been described, The frequency of these mutations has been investigated in a large sample of 51 Italian and Spanish cystinuric patients. In addition, to identify new mutated alleles, genomic DNA has been analyzed by an accurate and sensitive me thod able to detect nucleotide changes. Because of the lack of informa tion available on the genomic structure of rBAT gene, the study was ca rried out using the sequence data so far obtained by us. More than 70% of the entire coding sequence and 8 intronexon boundaries have been a nalyzed. Four new mutations and seven intragenic polymorphisms have be en detected. All mutations so far identified in rBAT belong only to cy stinuria type I alleles, accounting for similar to 44% of all type I c ystinuric chromosomes. Mutation M467T is the most common mutated allel e in the Italian and Spanish populations, After analysis of 70% of the rBAT coding region, we have detected normal sequences in cystinuria t ype II and type III chromosomes. The presence of rBAT mutated alleles only in type I chromosomes of homozygous (type I/I) and heterozygous ( type I/III) patients provides evidence for genetic heterogeneity where rBAT would be responsible only for type I cystinuria and suggests a c omplementation mechanism to explain the intermediate type I/type III p henotype.